The heritability of alcoholism is 40-60% in both men and women, however, as in other complex psychiatric diseases, it has proved difficult to identify causative genes. Intermediate phenotypes are associated biological traits that may be influenced by variation at fewer genes and may mediate different aspects of the disease. The intermediate phenotypes we are studying include dimensional anxiety (harm avoidance (HA)), resting EEG phenotypes, event-related potentials (ERPs) and heart rate variability (HRV). We have two large intermediate datasets: 247 US Caucasians and 365 Plains American Indians, a high alcoholism prevalence tribe. We have identified an intermediate phenotype for alcoholism vulnerability, the low voltage alpha (LVA) EEG, a normal, traitlike heritable variant of the resting EEG, present in 7-14% of the population, in which the alpha rhythm is virtually absent. We have shown that LVA is associated with alcoholism, particularly when accompanied by anxiety disorders (Enoch et al 1995,1999). Moreover, we found that LVA individuals, irrespective of clinical state, had reduced auditory and visual P300 ERP amplitudes, further strengthening our argument for the association of LVA with alcoholism vulnerability (Enoch et al 2002). As expected, P300 amplitude was reduced in alcoholics, however, it was lowest in alcoholics with comorbid anxiety disorders (Enoch et al 2001). Further analyses have shown that individuals who have anxiety disorders comorbid with alcoholism and/or major depression have higher HA and neuroticism but lower P300 amplitude than individuals with anxiety disorders alone (Enoch et al, submitted). We are undertaking candidate gene analyses and have found that in both Caucasian and Plains Indian women, the low activity Met allele (and particularly the Met/Met homozygote) of the catechol-O-methyltransferase (COMT) Val158Met functional polymorphism is associated both with LVA and HA (Enoch et al, 2003). Moreover, in this tribe the COMT Met/Met genotype is protective against alcoholism and the Met158 allele is protective against smoking in women (Enoch et al, submitted). We have also found that LVA is associated with the DRD2 functional promoter polymorphism, -141CIns/Del. We have recently found associations between HA and BDNF functional variants (Jiang et al, 2005) and between alcoholism, mediated by HA, and an HNMT functional variant (Oroszi et al, 2005). We have completed the collection of another large dataset including EEG and ERP phenotypes, HRV, blind-rated DSM-IV psychiatric diagnoses, personality tests, demographics and DNA on 198 members of a Southeastern American Indian tribe with a low rate of alcoholism and other psychiatric disorders. The processing of EEG, ERP and HRV data is almost complete. Our intention is to compare the low and high alcoholism prevalence tribes for gene x environment interactions. Formerly titled "Genetic studies of the electroencephalogram and event-related potentials" and "Genetic studies of EEG and ERP traits related to alcoholism".